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Cardiac mitochondrial function depends on BUD23 mediated ribosome programming

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Cite this article as: eLife 2020;9:e50705 doi: 10.7554/eLife.50705

Abstract

Efficient mitochondrial function is required in tissues with high energy demand such as the heart, and mitochondrial dysfunction is associated with cardiovascular disease. Expression of mitochondrial proteins is tightly regulated in response to internal and external stimuli. Here we identify a novel mechanism regulating mitochondrial content and function, through BUD23-dependent ribosome generation. BUD23 was required for ribosome maturation, normal 18S/28S stoichiometry and modulated the translation of mitochondrial transcripts in human A549 cells. Deletion of Bud23 in murine cardiomyocytes reduced mitochondrial content and function, leading to severe cardiomyopathy and death. We discovered that BUD23 selectively promotes ribosomal interaction with low GC-content 5'UTRs. Taken together we identify a critical role for BUD23 in bioenergetics gene expression, by promoting efficient translation of mRNA transcripts with low 5'UTR GC content. BUD23 emerges as essential to mouse development, and to postnatal cardiac function.

Article and author information

Author details

  1. Matthew Baxter

    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
    For correspondence
    matthew.baxter@ocdem.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3612-2574
  2. Maria Voronkov

    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Toryn Poolman

    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Gina Galli

    Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Christian Pinali

    Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Laurence Goosey

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Abigail Knight

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Karolina Krakowiak

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Robert Maidstone

    Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Mudassar Iqbal

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Min Zi

    Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Sukhpal Prehar

    Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Elizabeth J Cartwright

    Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Julie Gibbs

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Laura C Matthews

    Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Antony D Adamson

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Neil E Humphreys

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. Pedro Rebelo-Guiomar

    Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Michal Minczuk

    Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8242-1420
  20. David A Bechtold

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  21. Andrew Loudon

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  22. David Ray

    OCDEM, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, United Kingdom
    For correspondence
    david.ray@ocdem.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Funding

Medical Research Council (MR/L010240/1)

  • David Ray

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were carried out in strict accordance with the Animals (Scientific Procedures) Act 1986 (UK) and protocols were approved by an internal ethics committee at the University of Manchester. Every effort was made to minimize suffering. Home office project licence 70/8768 and P3A97F3D1.

Reviewing Editor

  1. Ulrike Topf, Institute of Biochemistry and Biophysics Polish Academy of Sciences, Poland

Publication history

  1. Received: July 30, 2019
  2. Accepted: December 24, 2019
  3. Accepted Manuscript published: January 15, 2020 (version 1)
  4. Version of Record published: February 5, 2020 (version 2)

Copyright

© 2020, Baxter et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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